Layer‐Specific Dermal and Subcutaneous Delivery via Modular LNP–Hydrogel‐Integrated Threaded Microneedles

Skin diseases exhibit hierarchical pathological remodeling across the epidermis, dermis, and subcutaneous tissue. However, current therapies lack precise and controllable layer-specific intervention. Here, we present a threaded microneedle-mRNA platform enabling stratified, targeted delivery. Guided by spatial transcriptomics and clinical validation, we identified layer-specific targets in skin fibrosis. Optimized lipid nanoparticles (LNPs) were integrated into a microneedle design featuring a fast-releasing superficial hydrogel that delivers a SIRT1 agonist to mitigate dermal fibroblast senescence, and helical grooves that directionally deposit PGC1α mRNA-LNPs into subcutaneous adipose during rotational insertion for in situ expression and reversal of adipocyte fibrotic phenotypes. In bleomycin-induced murine fibrosis, the system reduced dermal senescence and ECM deposition, restored subcutaneous adipose architecture, and attenuated overall fibrosis. This layer-specific microneedle-mRNA strategy offers a precise therapeutic pathway for complex skin diseases.